WO2019113642A1 - Utilisation d'un inhibiteur de fxiia dans le traitement d'une fibrose rénale et/ou d'une maladie rénale chronique - Google Patents

Utilisation d'un inhibiteur de fxiia dans le traitement d'une fibrose rénale et/ou d'une maladie rénale chronique Download PDF

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Publication number
WO2019113642A1
WO2019113642A1 PCT/AU2018/051333 AU2018051333W WO2019113642A1 WO 2019113642 A1 WO2019113642 A1 WO 2019113642A1 AU 2018051333 W AU2018051333 W AU 2018051333W WO 2019113642 A1 WO2019113642 A1 WO 2019113642A1
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Prior art keywords
fxii
inhibitor
seq
set forth
antibody
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PCT/AU2018/051333
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English (en)
Inventor
Malgorzata Wygrecka
Marc Nolte
Con Panousis
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Csl Limited
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Application filed by Csl Limited filed Critical Csl Limited
Priority to CN201880080931.3A priority Critical patent/CN111479587B/zh
Priority to AU2018382222A priority patent/AU2018382222A1/en
Priority to US16/772,207 priority patent/US11505619B2/en
Priority to KR1020207020386A priority patent/KR20200100116A/ko
Priority to CA3085478A priority patent/CA3085478A1/fr
Priority to EP18889862.1A priority patent/EP3723804A4/fr
Priority to JP2020531919A priority patent/JP7317827B2/ja
Priority to BR112020011240-2A priority patent/BR112020011240A2/pt
Publication of WO2019113642A1 publication Critical patent/WO2019113642A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/55—Protease inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/55—Protease inhibitors
    • A61K38/57—Protease inhibitors from animals; from humans
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A61K47/60—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/81—Protease inhibitors
    • C07K14/8107—Endopeptidase (E.C. 3.4.21-99) inhibitors
    • C07K14/811—Serine protease (E.C. 3.4.21) inhibitors
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/81—Protease inhibitors
    • C07K14/8107—Endopeptidase (E.C. 3.4.21-99) inhibitors
    • C07K14/811—Serine protease (E.C. 3.4.21) inhibitors
    • C07K14/8135—Kazal type inhibitors, e.g. pancreatic secretory inhibitor, ovomucoid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/36—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against blood coagulation factors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/55—Fab or Fab'
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding

Definitions

  • the present disclosure relates to a method of treating or preventing a renal or kidney disease.
  • CKD chronic kidney disease
  • UUO unilateral ureteral obstruction
  • Macrophages can affect kidney injury through the following mechanisms: i) boosting the inflammatory response by releasing an abundance of proinflammatory mediators, ii) macrophage-derived reactive oxygen species and TNF- a can trigger apoptosis and necrosis of TECs, therefore magnifying the renal injury, and iii) overproduction of profibrotic cytokines and growth factors by macrophages may stimulate proliferation of fibroblasts and their differentiation to a-smooth muscle actin (SMA)-positive myofibroblasts thereby inducing abnormal wound healing and finally fibrosis.
  • SMA smooth muscle actin
  • the detrimental role of macrophages in the pathogenesis of kidney diseases is also supported by the studies demonstrating that depletion of macrophages halts the development of crescentic glomerulonephritis and adoptive transfer of bone marrow-derived macrophages aggravates renal injury in the same disease model.
  • the UUO model is e.g. described in Chevalier et al. , Kidney International (2009), 75, 1145-1152 (doi:10.1038/ki.2009.86).
  • the contact system or plasma kallikrein-kinin system, consists of three serine proteases: Hageman factor (coagulation factor XII, FXII), factor XI (FXI), and plasma kallikrein (PKLK), and the nonenzymatic co-factor high molecular weight kininogen (HK).
  • Hageman factor coagulation factor XII, FXII
  • factor XI factor XI
  • PKLK plasma kallikrein
  • HK plasma kallikreinogen
  • Activation of the contact system occurs upon exposure of FXII to negatively charged surfaces such as kaolin, dextran sulphate, endotoxin, extracellular RNA, polyphosphates, and heparin.
  • FXII is converted into a two-chain, active protease, FXI la.
  • FXI la initiates the intrinsic blood coagulation pathway via activation of factor XI (FXI).
  • FXI factor XI
  • Recent data support the notion that FXII is dispensable for physiologic haemostasis, and demonstrate an essential role of FXII in pathologic thrombosis.
  • FXI la converts prekallikrein to kallikrein, which in turn activates additional FXII and liberates bradykinin (BK) from high-molecular weight kininogen (HK).
  • BK bradykinin
  • HK high-molecular weight kininogen
  • FXII stimulates the proliferation of endothelial cells in an uPAR-dependent manner.
  • Prior art publication WO 2006/066878 relates to the use of an anti-FXII antibody for inhibiting coagulation factor XII, as well as the use of a corresponding antibody or inhibitor in the treatment or prophylaxis of disorders related to venous or arterial thrombus formation, i.e. as an anti-thrombotic agent.
  • Prior art publication WO 2011/121 123 A1 relates to the use of Factor XII inbitors for treating interstitial lung disease.
  • C1 INH human C1 inhibitor
  • IRI ischaemia-reperfusion injury
  • the present invention provides
  • FXII Factor XII
  • FXII anti-Factor XII
  • chronic kidney disease and/or renal fibrosis in a subject in particular in a human or animal subject, in particular wherein the chronic kidney disease and/or renal fibrosis is a result of and/or is associated with one or more of the following: glomerulosclerosis, renal scarring, ischemia/reperfusion injury in kidneys, acute kidney injury, rejection of a kidney transplant/allograft, a recurrent underlying disease, and/or an inflammatory kidney disease related to FXII/FXI la-mediated complement formation, selected from the group not limited to Nephritides, Lupus-Nephritis, C3-Glomerulonephritis, Dense Deposit Disease, atypical haemolytic-uremic syndrome, post-streptococcal glomerulonephritis, Henoch-Schoenlein Purpura and antibody-mediated rejection of a kidney transplant.
  • glomerulosclerosis renal scarring
  • ischemia/reperfusion injury in kidneys acute kidney injury, rejection
  • the term“inhibitor of Factor XII” shall be understood so as to not encompass C1 INH, i.e.“with the proviso that the inhibitor of Factor XII is not CI INH”.
  • the inventors have studied the effects of inhibiting Factor XII (FXII) in a mouse model of renal fibrosis using the above-mentioned experimental model of unilateral ureteral obstruction (UUO). The inventors found that FXII inhibition in experimental renal fibrosis
  • the findings by the inventors provide the basis for methods for treating or preventing renal fibrosis and/or chronic kidney disease (CKD) in a subject by inhibiting FXII.
  • the findings by the inventors also provide the basis for an inhibitor of FXII for use in treating or preventing renal fibrosis and/or CKD in a subject.
  • the present disclosure provides a method for treating renal fibrosis and/or CKD in a subject comprising administering to the subject an inhibitor of FXII.
  • the disclosure provides a method for preventing renal fibrosis in a subject, the method comprising administering to the subject an inhibitor of FXII.
  • the present disclosure provides an inhibitor of FXII for use in treating renal fibrosis in a subject. In another example, the disclosure provides an inhibitor of FXII for use in preventing renal fibrosis in a subject.
  • the present disclosure additionally provides a method for or an inhibitor of FXII for use in reducing the progression of renal fibrosis in a subject.
  • the present disclosure provides a method for or an inhibitor of FXII for use in reducing the risk of or preventing renal fibrosis in a subject.
  • the inhibitor of FXII is a direct inhibitor. In one example, the inhibitor of FXII binds to FXII and/or FXIIa. In one example, the inhibitor of FXII binds to FXII and/or FXIIa and inhibits the activity of FXII and/or FXIIa. For example, the inhibitor of FXII binds to FXIIa and inhibits the activity of FXIIa. In another example, the inhibitor of FXII binds to FXII and inhibits FXII activation.
  • the activity of FXII and/or FXIIa is inhibited by at least about 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%, respectively.
  • the activity of FXII and/or FXIIa is inhibited by respectively about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100%.
  • Methods for determining the activity of FXII and/or FXIIa are known in the art and/or described herein.
  • the inhibitor of FXII is a serine protease inhibitor.
  • the FXII inhibitor is lnfestin-4.
  • the FXII inhibitor is SPINK-1.
  • the FXII inhibitor is an lnfestin-4 or SPINK-1 variant.
  • the inhibitor of FXII is not a serine protease inhibitor.
  • the inhibitor of FXII is not lnfestin-4.
  • the inhibitor of FXII is not a variant of lnfestin-4.
  • the inhibitor of FXII is not SPINK-1.
  • the inhibitor of FXII is not a variant of SPINK-1.
  • the method of or the inhibitor of FXII for use in the present disclosure comprises administering an inhibitor of FXII, wherein the inhibitor comprises:
  • SEQ ID NO: 2 mutated to replace N-terminal amino acid positions 2-13 with the N-terminal amino acids 2-13 of SEQ ID NO: 1 ; and optionally further modified to contain 1-5 additional amino acid mutations that increase the homology of the polypeptide sequence to the sequence of SEQ ID NO: 1 ; and/or
  • the inhibitor of FXII comprises the sequence of the serine protease inhibitor lnfestin-4.
  • the inhibitor of FXII comprises the sequence set forth in SEQ ID NO: 1.
  • the inhibitor of FXII comprises a modified lnfestin-4.
  • the inhibitor of FXII comprises the sequence set forth in SEQ ID NO: 1 modified to contain 1-5 amino acid mutations outside of N-terminal amino acid positions 2-13 of SEQ ID NO: 1.
  • the inhibitor of FXII comprises a sequence with at least 70% identity to the sequence set forth in SEQ ID NO: 1 and retaining six conserved cysteine residues from SEQ ID NO: 1.
  • the inhibitor of FXII has an identity of about 75% to SEQ I D NO: 1 , or an identity of about 80% to SEQ I D NO: 1 , or an identity of about 85% to SEQ ID NO: 1 , or an identity of about 90% to SEQ ID NO: 1 , or an identity of about 95% to SEQ ID NO: 1 , or an identity of about 98% to SEQ ID NO: 1 , or an identity of about 99% to SEQ ID NO: 1.
  • the inhibitor of FXII comprises the sequence of the serine protease inhibitor SPINK-1.
  • the inhibitor of FXII comprises the sequence set forth in SEQ ID NO: 2.
  • the inhibitor of FXII comprises the sequence set forth in SEQ ID NO: 2 mutated to replace N-terminal amino acid positions 2-13 with the N-terminal amino acids 2- 13 of SEQ ID NO: 1 ; and optionally further modified to contain 1-5 additional amino acid mutations that increase the homology of the polypeptide sequence to sequence of SEQ ID NO: 1.
  • the inhibitor of FXII comprises a sequence with at least 70% identity to the sequence set forth in SEQ ID NO: 2 and retaining six conserved cysteine residues from SEQ ID NO: 2.
  • the inhibitor of FXII has an identity of about 75% to SEQ ID NO: 2, or an identity of about 80% to SEQ ID NO: 2, or an identity of about 85% to SEQ ID NO: 2, or an identity of about 90% to SEQ ID NO: 2, or an identity of about 95% to SEQ ID NO: 2, or an identity of about 98% to SEQ ID NO: 2, or an identity of about 99% to SEQ ID NO: 2.
  • the inhibitor of FXII is a protein comprising a variable region fragment (Fv).
  • the protein is selected from the group consisting of:
  • scFv single chain Fv fragment
  • di-scFv dimeric scFv
  • a diabody i.e. a bispecific antibody
  • a triabody i.e. a trispecific antibody
  • a tetrabody i.e. a tetraspecific antibody
  • (x) one of (i) to (ix) linked to a constant region of an antibody, Fc or a heavy chain constant domain (CH) 2 and/or CH3; or
  • an inhibitor of FXII is an antibody.
  • the antibody is an anti- FXII antibody.
  • the antibody is an anti-FXIIa antibody.
  • Exemplary antibodies are full-length and/or naked antibodies.
  • the inhibitor of FXII is a protein that is recombinant, chimeric, CDR grafted, humanized, synhumanized, primatized, deimmunized or human.
  • the antibody is an IgG antibody.
  • the anti-FXII antibody comprises a heavy chain variable region (VH) comprising a sequence set forth in SEQ ID NO: 6. In one example, the anti-FXII antibody comprises a light chain variable region (VL) comprising a sequence set forth in SEQ ID NO: 7.
  • the anti-FXII antibody comprises a V H comprising a sequence set forth in SEQ ID NO: 6 and a V L comprising a sequence set forth in SEQ ID NO: 7.
  • the anti-FXII antibody comprises a variable region comprising the complementary determining regions (CDRs) of the V H and/or the V L of SEQ ID NO: 6 and SEQ ID NO: 7.
  • the protein or antibody is any form of the protein or antibody encoded by a nucleic acid encoding any of the foregoing proteins or antibodies, such as a variant missing an encoded C-terminal lysine residue, a deamidated variant and/or a glycosylated variant and/or a variant comprising a pyroglutamate, e.g. , at the N-terminus of a protein and/or a variant lacking a N-terminal residue.
  • the anti-FXII antibody comprises:
  • VH comprising:
  • a CDR1 comprising a sequence set forth in SEQ ID NO: 8; a CDR2 comprising a sequence set forth in SEQ ID NO: 10; and a CDR3 comprising a sequence set forth in SEQ ID NO: 12; or (c) a CDR1 comprising a sequence set forth in SEQ ID NO: 8; a CDR2 comprising a sequence set forth in SEQ ID NO: 9; and a CDR3 comprising a sequence set forth in SEQ ID NO: 11 ; and/or
  • VL comprising:
  • the anti-FXII antibody comprises:
  • VH comprising:
  • VL comprising:
  • the anti-FXII antibody comprises:
  • V H comprising:
  • V L comprising:
  • the anti-FXII antibody comprises:
  • the anti-FXII antibody comprises a V H comprising a sequence set forth in SEQ ID NO: 18 and a VL comprising a sequence set forth in SEQ ID NO: 19.
  • the anti-FXII antibody comprises lambda light chain constant regions.
  • the anti-FXII antibody comprises lgG4 or stabilized lgG4 constant regions.
  • the stabilized lgG4 constant regions comprise a proline at position 241 of the hinge region according to the system of Kabat (Kabat et a!., Sequences of Proteins of Immunological Interest Washington DC United States Department of Health and Human Services, 1987 and/or 1991).
  • the anti-FXII antibody is within a composition.
  • the composition comprises a protein comprising an antibody variable region or a VH or a VL or an antibody as described herein.
  • the composition additionally comprises one or more variants of the protein or antibody.
  • a deamidated variant and/or a glycosylated variant and/or a variant comprising a pyroglutamate e.g., at the N-terminus of a protein and/or a variant lacking a N-terminal residue, e.g., a N-terminal glutamine in an antibody or V region and/or a variant comprising all or part of a secretion signal.
  • Deamidated variants of encoded asparagine residues may result in isoaspartic, and aspartic acid isoforms being generated or even a succinamide involving an adjacent amino acid residue.
  • Deamidated variants of encoded glutamine residues may result in glutamic acid.
  • Compositions comprising a heterogeneous mixture of such sequences and variants are intended to be included when reference is made to a particular amino acid sequence.
  • the inhibitor of FXII is linked to a fusion partner.
  • the fusion partner comprises polyethylene glycol (PEG) or a half-life enhancing polypeptide.
  • the inhibitor of FXII is linked to the fusion partner directly. In another example, the inhibitor of FXII is linked to the fusion partner via a linker.
  • the inhibitor of FXII is linked to a half-life enhancing polypeptide directly. In another example, the inhibitor of FXII is linked to a half-life enhancing polypeptide via a linker.
  • the inhibitor of FXII is linked to the PEG directly. In another example, the inhibitor of FXII is linked to the PEG via a linker.
  • the linker is an intervening peptidic linker.
  • the linker is a cleavable linker.
  • the half-life enhancing polypeptide is selected from the group consisting of albumin, afamin, alpha-fetoprotein, vitamin D binding protein, human albumin, an immunoglobulin, and an Fc of an IgG.
  • the half-life enhancing polypeptide is albumin.
  • the inhibitor of FXII is a fusion protein comprising human albumin linked to a FXII inhibitor via a linker peptide.
  • the inhibitor of FXII is administered parenterally.
  • the inhibitor of FXII is administered intravenously, or subcutaneously, or intrathecal.
  • the inhibitor of FXII is administered subcutaneously.
  • the inhibitor of FXII is administered intravenously.
  • the inhibitor of FXII is administered to the subject in one or more doses.
  • the inhibitor of FXII is administered to the subject:
  • the inhibitor of FXII is administered to the subject in a single dose.
  • the inhibitor of FXII is administered to the subject in a plurality of doses.
  • the inhibitor of FXII is administered to the subject as two doses, or three doses, or four doses, or five doses or more.
  • administration of each dose of the inhibitor of FXII is separated by a period of hours.
  • administration of each dose of the inhibitor of FXII is separated by the period of about 1 hour, or about 2 hours, or about 3 hours, or about 4 hours, or about 6 hours, or about 8 hours, or about 12 hours, or about 16 hours, or about 20 hours, or about 24 hours.
  • administration of each dose of the inhibitor of FXII is separated by a period of days.
  • administration of each dose of the inhibitor of FXII is separated by the period of about 1 day, or about 2 days, or about 3 days, or about 4 days, or about 5 days, or about 6 days, or about 7 days.
  • administration of each dose of the inhibitor of FXII is separated by at least 14 days or at least 28 days.
  • administration of each dose of the inhibitor of FXII is separated by a period of weeks.
  • administration of each dose of the inhibitor of FXII is separated by the period of about 1 week, or about 2 weeks, or about 3 weeks, or about 4 weeks, or about 5 weeks, or about 6 weeks.
  • administration of each dose of the inhibitor of FXII is separated by at least one month.
  • the length of time between administrations of the inhibitor of FXII is the same throughout the course of administration. In one example, the length of time between administrations of the inhibitor of FXII is different throughout the course of administration. For example, the inhibitor of FXII is administered on a weekly basis at the commencement of therapy and then on a monthly basis following a predetermined number of doses. In one example, the length of time between administrations of the inhibitor of FXII is variable.
  • the inhibitor of FXII is administered to the subject as a continuous dose.
  • the inhibitor of FXII is administered to the subject as a continuous infusion over a period of time.
  • the inhibitor of FXII is administered over a period of between about 1 minute to about 24 hours.
  • the inhibitor of FXII is administered over a period of about 10 minutes to about 12 hours, or about 10 minutes to about 6 hours, or about 10 minutes to about 5 hours, or about 10 minutes to about 4 hours, or about 10 minutes to about 3 hours, or about 10 minutes to about 2 hours, or about 10 minutes to about 1 hour, or about 30 minutes.
  • the inhibitor of FXII is administered a plurality of times.
  • the inhibitor of FXII is administered one or more times.
  • the inhibitor of FXII is administered until the renal fibrosis is treated or prevented.
  • the inhibitor of FXII is administered for a period of days to months.
  • the inhibitor of FXII is administered for about one day, or about 2 days, or about 3 days, or about 4 days, or about 5 days, or about 6 days, or about 1 week, or about 2 weeks, or about 4 weeks, or about six weeks, or about 2 months.
  • the inhibitor of FXII is administered in a therapeutically or prophylactically effective amount.
  • the inhibitor of FXII is administered to the subject at a dose of about 0.01 mg/kg to about 1000 mg/kg.
  • the inhibitor of FXII is administered at a dose of about 0.01 mg/kg bodyweight, or about 0.1 mg/kg bodyweight, or about 1 mg/kg bodyweight, or about 50 mg/kg bodyweight, or about 100 mg/kg bodyweight, or about 200 mg/kg bodyweight, or about 500 mg/kg bodyweight, or about 1000 mg/kg bodyweight.
  • the inhibitor of FXII is administered at a dose of about 0.001 mg/kg to about 100 mg/kg body weight, or about 0.01 mg/kg to about 100 mg/kg, or about 0.01 mg/kg to about 50 mg/kg, or about 0.1 mg/kg to about 30 mg/kg, or about 0.1 mg/kg to about 10 mg/kg, or about 0.1 mg/kg to about 5 mg/kg, or about 0.1 mg/kg to about 2 mg/kg or about 0.1 mg/kg to about 1 mg/kg.
  • the inhibitor of FXII is administered at a dose ranging from about 0.01 mg/kg to about 1000 mg/kg, or about 0.1 mg/kg to about 1000 mg/kg, or about 1 mg/kg to about 1000 mg/kg, or about 1 mg/kg to about 500 mg/kg, or about 10 mg/kg to about 200 mg/kg, or about 10 mg/kg to about 100 mg/kg, or about 50 mg/kg to about 500 mg/kg, or about 50 mg/kg to about 200 mg/kg, or about 100 mg/kg to about 200 mg/kg.
  • the inhibitor of FXII is administered at a dose of about 10 mg/kg. In one example, the inhibitor of FXII is administered at a dose of about 20 mg/kg.
  • the subject has renal fibrosis and/or chronic kidney disease (CKD). In one example, the subject has been diagnosed as suffering from renal fibrosis and/or CKD. In one example, the subject is receiving treatment for renal fibrosis and/or CKD. In one example, the subject is receiving treatment for a renal fibrosis and/or CKD associated condition (e.g. diabetic nephropathy, hypertensive nephropathy, glomerulonephritis, glomerulosclerosis, interstitial nephritis). In one example, the patient is receiving treatment for a native or allograft kidney fibrosis and/or CKD.
  • CKD chronic kidney disease
  • the subject is receiving treatment with an ACE-inhibitor, an antihypertensive, a corticosteroid, an immunosuppressive agent (Azathioprine, MMF, Cyclophosphamide, Rituximab).
  • an ACE-inhibitor an antihypertensive
  • a corticosteroid an immunosuppressive agent
  • an immunosuppressive agent Azathioprine, MMF, Cyclophosphamide, Rituximab
  • the subject is receiving treatment in the form of dialysis or hemodialysis. In one example the subject is receiving treatment with a RAAS-inhibitor.
  • the subject is at risk of developing renal fibrosis and/or CKD.
  • the inhibitor of FXII is used in a preventative or prophylactic manner or can be said to be used in a primary preventative manner.
  • An exemplary subject at risk of developing renal fibrosis and/or CKD suffers from diabetes.
  • the diabetes is type 2 diabetes.
  • Additional or alternative characteristics of a subject at risk of suffering from renal fibrosis and/or CKD include one or more of the following characteristics:
  • a subject with hypertenisive nephropathy (nephrosclerosis) at risk of developing renal fibrosis and/or chronic kidney disease (CKD) is treated with the inhibitor of FXIIa to suppress fibrogenesis.
  • a subject with chronic glomerulonephritis at risk of developing renal fibrosis and/or CKD is treated with the inhibitor of FXII to prevent kidney fibrosis.
  • a subject suffering from Alport syndrome at risk of developing renal fibrosis and/or CKD is treated with the inhibitor of FXII to reduce renal fibrosis.
  • Patients suffering from renal vasculitis have intensive renal inflammation both in glomeruli and in the tubulo-interstitium with elvatded levels of acute phase inflammatory markers: Increased levels of C-reactive protein and IL-6 in the circulation.
  • the inhibitor of FXII is administered to the subject before or after the onset of renal fibrosis and/or CKD.
  • the inhibitor of FXII is administered prophylactically or therapeutically.
  • the inhibitor is administered to the subject prophylactically.
  • the inhibitor is administered to the subject therapeutically.
  • the present disclosure provides a method for reducing the risk of having to undergo dialysis and/or a kidney transplant by performing a method described herein.
  • the inhibitor of FXII is administered to patients with diabetic nephropathy in an amount sufficient to elicit the following effects: Reduction of proteinuria and slowing the loss of glomerular filtration rate (GFR).
  • the inhibitor of FXII is administered in patients suffering from early glomerulosclerosis before the development of renal fibrosis and/or CKD in order to prevent renal fibrosis with end stage renal disease.
  • the inhibitor of FXII is administered after the development of renal fibrosis and/or CKD in order to investigate whether the further loss of GFR can be slowed.
  • the inhibitor of FXIIa is administered after the onset of symptoms of renal fibrosis and/or chronic kidney disease (CKD) in order to examine whether proteinurie can be reduced.
  • the inhibitor of FXII is administered at a dose that alleviates or reduces one or more of the symptoms of renal fibrosis and/or CKD, such as proteinuria and loss of GFR.
  • Methods of treatment or inhibitors of FXII for use described herein may additionally reduce the need of administering corticosteroids and other immunosuppressive agents (Azathioprine, MMF, Cyclophosphamide, Rituximab) for preventing and/or treating renal fibrosis and/or CKD.
  • corticosteroids and other immunosuppressive agents Azathioprine, MMF, Cyclophosphamide, Rituximab
  • the present disclosure also provides a composition comprising an inhibitor of FXII for use in treating or preventing renal fibrosis and/or CKD in a subject in need thereof.
  • the present disclosure also provides use of an inhibitor of FXII in the manufacture of a medicament for treating or preventing renal fibrosis and/or CKD in a subject.
  • the present disclosure also provides a kit comprising at least one inhibitor of FXII packaged with instructions for use in treating or preventing renal fibrosis and/or CKD in a subject.
  • the kit additionally comprises a therapeutically active compound or drug.
  • the present disclosure also provides a kit comprising at least one inhibitor of FXII packaged with instructions to administer the inhibitor of FXI I to a subject who is suffering from or at risk of suffering from renal fibrosis and/or CKD, optionally, in combination with a therapeutically active compound or drug.
  • kidney fibrosis and/or chronic kidney disease (CKD) and inhibitors of FXII are described herein and are to be taken to apply mutatis mutandis to the examples of the disclosure set out in the previous five paragraphs.
  • an inhibitor of FXII e.g., an anti-FXII antibody or antigen binding fragment thereof suitable for use in treating a human subject.
  • This inhibitor is an affinity matured human antibody that has been modified to make most, but not all, residues in the framework regions the same as those in a germline human antibody thereby reducing the potential for immunogenicity.
  • This antibody is also capable of inhibiting FXI la and has good manufacturability characteristics.
  • the present disclosure also provides an anti-FXII antibody or antigen binding fragment thereof, wherein the anti-FXII antibody comprises a VH comprising a sequence set forth in SEQ ID NO: 18 and a VL comprising a sequence set forth in SEQ ID NO: 19.
  • the anti-FXII antibody comprises lambda light chain constant regions.
  • the anti-FXII antibody comprises lgG4 or stabilized lgG4 constant regions.
  • the stabilized lgG4 constant regions comprise a proline at position 241 of the hinge region according to the system of Kabat (Kabat et a!., Sequences of Proteins of Immunological Interest Washington DC United States Department of Health and Human Services, 1987 and/or 1991).
  • the anti-FXII antibody comprises a heavy chain comprising a sequence set forth in SEQ ID NO: 20 and a light chain comprising a sequence set forth in SEQ ID NO: 21.
  • the disclosure provides a composition comprising the anti-FXII antibody or antigen binding fragment and a carrier, e.g., a pharmaceutically acceptable carrier.
  • the composition additionally comprises one or more variants of the protein or antibody.
  • a deamidated variant and/or a glycosylated variant and/or a variant comprising a pyroglutamate e.g., at the N-terminus of a protein and/or a variant lacking a N-terminal residue, e.g., a N-terminal glutamine in an antibody or V region and/or a variant comprising all or part of a secretion signal.
  • Deamidated variants of encoded asparagine residues may result in isoaspartic, and aspartic acid isoforms being generated or even a succinamide involving an adjacent amino acid residue.
  • Deamidated variants of encoded glutamine residues may result in glutamic acid.
  • Compositions comprising a heterogeneous mixture of such sequences and variants are intended to be included when reference is made to a particular amino acid sequence.
  • the present disclosure also provides the anti-FXII antibody or antigen binding fragment thereof for medical use.
  • the present disclosure also provides a method for treating or preventing a disorder in a subject, the method comprising administering the anti-FXII antibody or antigen binding fragment thereof, wherein the disorder is selected from the group consisting of renal diseases related to FXII/FXIIa-mediated complement activation.
  • kidney diseases related to FXII/FXIIa- induced complement activation will be selected for treatment with the FXII/FXI la- inhibitor.
  • the artificial surface is exposed to at least 100% of the blood volume of the subject and the artificial surface is at least 1.0 m 2 or
  • the artificial surface is a part of the extracorporeal circulation outside of the body of the subject or
  • the artificial surface is part of a dialysis equipment, such as the dialyzer membrane, tubing system, bubble-catcher and drip chambers (exposure of blood to air).
  • a medical device coated with the antibody or antigen-binding fragment of the invention wherein the device is a dialysis machine, an extracorporeal membrane oxygenation system for oxygenation of blood, a device for assisted pumping of blood, a blood dialysis device, a device for the extracorporeal filtration of blood, a repository for use in the collection of blood, an intraluminal catheter, a stent, and/or accessories for any one of said devices including tubing, cannulae, centrifugal pump, valve, port, and/or diverter.
  • the present disclosure also provides a method comprising administering the anti-FXII antibody or antigen binding fragment thereof to a patient receiving an extracorporeal procedure, wherein the medical procedure comprises contact with at least one of:
  • the present disclosure also provides a method for treating or preventing a condition associated with increased renal vascular permeability, including progressive nephrotic syndrome, protein-wasting diabetic nephropathy, wherein the method comprises administering the anti-FXII antibody or antigen binding fragment thereof.
  • Figure 1A is a representation of the tubular injury score determined in control and obstructed (UUO) kidneys from IgG- or 3F7-treated mice at day 10 post injury.
  • Figure 1 B shows PAS-stained sections from control and obstructed (UUO) kidneys from IgG- or 3F7-treated mice at day 10 post injury.
  • Figures 2A-C are representations of the expression of a-SMA as assessed by qPCR ( Figure 2A), western blotting ( Figure 2B) and immunohistochemistry (Figure 2C), in control and obstructed (UUO) kidneys from IgG- or 3F7-treated mice at day 10 post injury.
  • Figures 3A-C are representations of the expression of fibronectin as assessed by qPCR ( Figure 3A), western blotting (Figure 3B) and immunohistochemistry (Figure 3C), in control and obstructed (UUO) kidneys from IgG- or 3F7-treated mice at day 10 post injury.
  • Figures 4A-C are representations of expression of collagen I (Col I) as assessed by qPCR ( Figure 4A), hydroxyproline content ( Figure 4B) and immunohistochemistry (Figure 4C) in control and obstructed (UUO) kidneys from IgG- or 3F7-treated mice at day 10 post injury.
  • Figures 5A and 5B are representations of the accumulation of macrophages (F4/80 positive cells) in control and obstructed (UUO) kidneys from IgG- or 3F7-treated mice at day 10 post injury.
  • Figure 6 shows representative cleaved caspase-3-stained sections from control and obstructed (UUO) kidneys from IgG- or 3F7-treated mice at day 3 post injury.
  • Figure 7 shows representative Ki67-stained sections from control and obstructed (UUO) kidneys from IgG- or 3F7-treated mice at day 3 post injury.
  • Figure 8 shows representative PAS-stained sections from control and obstructed kidneys from IgG- or 3F7-treated mice at day 3 post injury.
  • Figure 9 represents the body weight loss of IgG- and 3F7-treated mice with control and obstructed (UUO) kidneys at day 10 post injury.
  • Figure 10 represents the ratio of kidney/body weight of IgG- and 3F7-treated mice with control and obstructed (UUO) kidneys at day 10 post injury.
  • SEQ ID NO: 1 is an amino acid sequence of wild-type lnfestin-4
  • SEQ ID NO: 2 an amino acid sequence of wild-type SPINK-1
  • SEQ ID NO: 3 an amino acid sequence of SPINK-1 mutant K1
  • SEQ ID NO: 4 an amino acid sequence of SPINK-1 mutant K2
  • SEQ ID NO: 5 an amino acid sequence of SPINK-1 mutant K3
  • SEQ ID NO: 6 s an amino acid sequence from the V H of anti-FXII antibody 3F7
  • SEQ ID NO: 7 s an amino acid sequence from the V L of anti-FXII antibody 3F7
  • SEQ ID NO: 8 s an amino acid sequence from a V H CDR1 of an anti-FXII antibody
  • SEQ ID NO: 9 s an amino acid sequence from a V H CDR2 of an anti-FXII antibody
  • SEQ ID NO: 10 is an amino acid sequence from a V H CDR2 of an anti-FXII antibody
  • SEQ ID NO: 11 is an amino acid sequence from a V H CDR3 of an anti-FXII antibody
  • SEQ ID NO: 12 is an amino acid sequence from a V H CDR3 of an anti-FXII antibody
  • SEQ ID NO: 13 is an amino acid sequence from a V L CDR1 of an anti-FXII antibody
  • SEQ ID NO: 14 is an amino acid sequence from a
  • SEQ ID NO: 17 is an amino acid sequence from a VL CDR1 of an anti-FXII antibody
  • SEQ ID NO: 18 is an amino acid sequence of the VH of anti-FXII antibody gVR115
  • SEQ ID NO: 19 is an amino acid sequence of the V L of anti-FXII antibody gVR1 15
  • SEQ ID NO: 20 is an amino acid sequence of the heavy chain of anti-FXII antibody gVR1 15
  • SEQ ID NO: 21 is an amino acid sequence of the light chain of anti-FXII antibody gVR1 15
  • SEQ ID NO: 22 is an amino acid sequence from a human Factor XII
  • SEQ ID NO: 23 is an amino acid sequence of a mature form of human albumin
  • SEQ ID NO: 24 is an amino acid sequence of an lnfestin-4 variant
  • SEQ ID NO: 25 is an amino acid sequence of an lnfestin-4 variant
  • composition of matter, group of steps or group of compositions of matter shall be taken to encompass one and a plurality (i.e. one or more) of those steps, compositions of matter, groups of steps or groups of compositions of matter.
  • variable regions and parts thereof, immunoglobulins, antibodies and fragments thereof herein may be further clarified by the discussion in Kabat Sequences of Proteins of Immunological Interest, National Institutes of Health, Bethesda, Md., 1987 and 1991 , Bork et al., J Mol. Biol. 242, 309-320, 1994, Chothia and Lesk J. Mol Biol. 196:901 -917, 1987, Chothia et al. Nature 342, 877-883, 1989 and/or or Al-Lazikani et al., J Mol Biol 273, 927-948, 1997. Any discussion of a protein or antibody herein will be understood to include any variants of the protein or antibody produced during manufacturing and/or storage.
  • an antibody can be deamidated (e.g., at an asparagine or a glutamine residue) and/or have altered glycosylation and/or have a glutamine residue converted to pyroglutamine and/or have a N-terminal or C-terminal residue removed or “clipped”and/or have part or all of a signal sequence incompletely processed and, as a consequence, remain at the terminus of the antibody.
  • a composition comprising a particular amino acid sequence may be a heterogeneous mixture of the stated or encoded sequence and/or variants of that stated or encoded sequence.
  • derived from shall be taken to indicate that a specified integer may be obtained from a particular source albeit not necessarily directly from that source.
  • Coagulation Factor XII also known as Hageman factor or FXII
  • FXII is a plasma protein. It is the zymogen form of Factor XI la, an enzyme of the serine protease (or serine endopeptidase) class.
  • Factor XII is encoded by the F12 gene.
  • exemplary sequences of human Factor XII is set out in NCBI Reference Sequence: NP_000496.2; in NCPI protein accession number NP_000496 and in SEQ ID NO: 22.
  • Factor XII Factor XIII
  • sequences provided herein and/or in publically available databases and/or determined using standard techniques (e.g., as described in Ausubel et a!., (editors), Current Protocols in Molecular Biology, Greene Pub. Associates and Wiley- Interscience (1988, including all updates until present) or Sambrook et a!., Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press (1989)).
  • the term“Factor XII inhibitor” or“FXII inhibitor”or“inhibitor of FXII” refers to an inhibitor of either or both of Factor XII (prior to activation, i.e. , its zymogen) and activated Factor XI I (FXIIa) as well as to the activation of FXII.
  • “inhibitor(s) of FXII” can include inhibitors of either or both of FXII and FXIIa (also termed aFXIIa) as well as the activation of FXII, including the FXIIa cleavage products FXIIa alpha and FXIIa beta (also termed FXIIf).
  • FXII inhibitors encompass functional variants and fragments of the wild-type inhibitor.
  • a functional variant or fragment is a molecule that retains at least 50% (e.g., about 50%, or about 60%, or about 70%, or about 80%, or about 90%, or about 95%, or about 99%, or about 100%) of the ability of the wild-type molecule to inhibit FXII, FXIIa or the activation of FXII.
  • the FXII inhibitors are non- endogenous inhibitors; that is, they are not inhibitors that occur naturally in the human or animal body.
  • direct FXII inhibitor refers to an inhibitor that acts via contact (e.g., binding) with FXII (or FXIIa), i.e., the FXII inhibitor binds to FXII and/or FXIIa and inhibits its activity and/or activation.
  • an indirect inhibitor may act without contacting FXII (or FXIIa) protein.
  • antisense RNA can be used to decrease expression of the FXII gene, or a small molecule can inhibit the effects of FXIIa via interactions with downstream FXIIa reaction partners like Factor XI; these do not interact directly with the FXII protein.
  • an indirect inhibitor in contrast to a direct inhibitor, acts upstream or downstream from the FXII protein.
  • the FXII inhibitors are specific to FXII or FXIIa, in particular specific to human FXII or FXIIa.
  • the term“inhibitor of Factor XII” or provisionFactor XII inhibitor” shall in addition be understood so as to not encompass C1-INH, i.e.“with the proviso that the inhibitor of Factor XII is not C1 INH”.
  • the term“binds” in reference to the interaction of a protein or an antigen binding site thereof with an antigen means that the interaction is dependent upon the presence of a particular structure (e.g., an antigenic determinant or epitope) on the antigen.
  • a particular structure e.g., an antigenic determinant or epitope
  • an antibody recognizes and binds to a specific protein structure rather than to proteins generally. If an antibody binds to epitope“A”, the presence of a molecule containing epitope“A” (or free, unlabeled“A”), in a reaction containing labeled “A” and the protein, will reduce the amount of labeled“A” bound to the antibody.
  • the term“specifically binds” or“binds specifically” shall be taken to mean that a protein or an antigen binding site thereof reacts or associates more frequently, more rapidly, with greater duration and/or with greater affinity with a particular antigen or cell expressing same than it does with alternative antigens or cells.
  • a protein or an antigen binding site thereof binds to FXII (or FXIIa) with materially greater affinity (e.g., 1.5 fold or 2 fold or 5 fold or 10 fold or 20 fold or 40 fold or 60 fold or 80 fold to 100 fold or 150 fold or 200 fold) than it does to other blood clotting factors or to antigens commonly recognized by polyreactive natural antibodies (i.e., by naturally occurring antibodies known to bind a variety of antigens naturally found in humans).
  • reference to binding means specific binding, and each term shall be understood to provide explicit support for the other term.
  • aminolytic activity refers to the ability of the inhibitor of FXII to catalyse the hydrolysis of at least one peptide bond in another polypeptide.
  • identity or “identical” as used herein refers to the percentage number of amino acids that are identical or constitute conservative substitutions. Homology may be determined using sequence comparison programs such as GAP (Deveraux et al. , 1984, Nucleic Acids Research 12, 387-395), which is incorporated herein by reference. In this way sequences of a similar or substantially different length to those cited herein could be compared by insertion of gaps into the alignment, such gaps being determined, for example, by the comparison algorithm used by GAP.
  • A“half-life enhancing polypeptide” or“HLEP” is a polypeptide fusion partner that may increase the half-life of the FXII inhibitor in vivo in a patient or in an animal.
  • examples include albumin and immunoglobulins and their fragments, such as Fc domains, or derivatives, which may be fused to a FXII inhibitor directly or via a cleavable or non- cleavable linker.
  • Ballance et al. (WO 2001/79271) described fusion polypeptides comprising a multitude of different therapeutic polypeptides fused to human serum albumin.
  • the terms“albumin” and“serum albumin” encompass human albumin (HA) and variants thereof.
  • albumin refers to an albumin polypeptide or amino acid sequence, or an albumin variant, having one or more functional activities (e.g. biological activities) of albumin.
  • albumin is used to stabilize or prolong the therapeutic activity of a FXI I inhibitor.
  • the albumin may be derived from any vertebrate, especially any mammal, for example human, monkey, cow, sheep, or pig.
  • Non-mammalian albumin can also be used and includes, but is not limited to, albumin from chicken and salmon.
  • the albumin portion of the albumin-linked polypeptide may be from a different animal than the therapeutic polypeptide portion. See WO 2008/098720 for examples of albumin fusion proteins, incorporated herein by reference in its entirety.
  • recombinant shall be understood to mean the product of artificial genetic recombination. Accordingly, in the context of a recombinant protein comprising an antibody variable region, this term does not encompass an antibody naturally-occurring within a subject’s body that is the product of natural recombination that occurs during B cell maturation. However, if such an antibody is isolated, it is to be considered an isolated protein comprising an antibody variable region. Similarly, if nucleic acid encoding the protein is isolated and expressed using recombinant means, the resulting protein is a recombinant protein. A recombinant protein also encompasses a protein expressed by artificial recombinant means when it is within a cell, tissue or subject, e.g., in which it is expressed.
  • protein shall be taken to include a single polypeptide chain, i.e. , a series of contiguous amino acids linked by peptide bonds or a series of polypeptide chains covalently or non-covalently linked to one another (i.e., a polypeptide complex).
  • the series of polypeptide chains can be covalently linked using a suitable chemical or a disulfide bond.
  • non-covalent bonds include hydrogen bonds, ionic bonds, Van der Waals forces, and hydrophobic interactions.
  • polypeptide or“polypeptide chain” will be understood from the foregoing paragraph to mean a series of contiguous amino acids linked by peptide bonds.
  • an“antibody” is generally considered to be a protein that comprises a variable region made up of a plurality of polypeptide chains, e.g., a polypeptide comprising a light chain variable region (VL) and a polypeptide comprising a heavy chain variable region (VH).
  • An antibody also generally comprises constant domains, some of which can be arranged into a constant region, which includes a constant fragment or fragment crystallizable (Fc), in the case of a heavy chain.
  • Fc constant fragment or fragment crystallizable
  • a light chain from mammals is either a Klight chain or a Alight chain and a heavy chain from mammals is a, d, e, g, or m.
  • Antibodies can be of any type (e.g., IgG, IgE, IgM, IgD, IgA, and IgY), class (e.g., lgG1 , lgG2, lgG3, lgG4, lgA1 and lgA2) or subclass.
  • the term“antibody” also encompasses humanized antibodies, primatized antibodies, human antibodies, synhumanized antibodies and chimeric antibodies.
  • an “anti-FXII antibody” includes antibodies that bind to and/or inhibit either or both of the zymogen of FXII and the activated protein (FXIIa), including the FXIIa alpha and FXIIa beta cleavage fragments. In some examples, the antibody binds specifically to FXIIa or the alpha or beta chain fragments of FXIIa.
  • full-length antibody “intact antibody” or “whole antibody” are used interchangeably to refer to an antibody in its substantially intact form, as opposed to an antigen binding fragment of an antibody.
  • whole antibodies include those with heavy and light chains including an Fc region.
  • the constant domains may be wild- type sequence constant domains (e.g., human wild-type sequence constant domains) or amino acid sequence variants thereof.
  • variable region refers to the portions of the light and/or heavy chains of an antibody as defined herein that is capable of specifically binding to an antigen and includes amino acid sequences of complementarity determining regions (CDRs); i.e., CDR1 , CDR2, and CDR3, and framework regions (FRs).
  • CDRs complementarity determining regions
  • FRs framework regions
  • Exemplary variable regions comprise three or four FRs (e.g., FR1 , FR2, FR3 and optionally FR4) together with three CDRs.
  • the protein may lack a CDR2.
  • VH refers to the variable region of the heavy chain.
  • VL refers to the variable region of the light chain.
  • CDRs complementarity determining regions
  • CDRI complementarity determining regions
  • CDR2 complementarity determining regions
  • Each variable domain typically has three CDR regions identified as CDR1 , CDR2 and CDR3.
  • the amino acid positions assigned to CDRs and FRs can be defined according to Kabat Sequences of Proteins of Immunological Interest, National Institutes of Health, Bethesda, Md., 1987 and 1991 or other numbering systems in the performance of this disclosure, e.g., the canonical numbering system of Chothia and Lesk J. Mol Biol.
  • FRs Framework regions
  • variable region fragment or“Fv” shall be taken to mean any protein, whether comprised of multiple polypeptides or a single polypeptide, comprising a VL and a VH, wherein the VL and a VH are associated to form a complex having an antigen binding site, i.e. , capable of specifically binding to an antigen.
  • the V H and the V L which form the antigen binding site can be in a single polypeptide chain or in different polypeptide chains.
  • an Fv of the disclosure (as well as any protein of the disclosure) may have multiple antigen binding sites which may or may not bind the same antigen.
  • VH is not linked to a heavy chain constant domain (CH) and/or the VL is not linked to a light chain constant domain (CL).
  • exemplary Fv containing polypeptides or proteins include a Fab fragment, a Fab’ fragment, a F(ab’) fragment, a scFv, a diabody, a triabody, a tetrabody or higher order complex, or any of the foregoing linked to a constant region or domain thereof, e.g., CH2 or CH3 domain, e.g., a minibody or an antibody.
  • A“Fab fragment” consists of a monovalent antigen binding fragment of an antibody, and can be produced by digestion of a whole antibody with the enzyme papain, to yield a fragment consisting of an intact light chain and a portion of a heavy chain or can be produced using recombinant means.
  • a “Fab 1 fragment” of an antibody can be obtained by treating a whole antibody with pepsin, followed by reduction, to yield a molecule consisting of an intact light chain and a portion of a heavy chain comprising a VH and a single constant domain. Two Fab' fragments are obtained per antibody treated in this manner.
  • a Fab’fragment can also be produced by recombinant means.
  • A“F(ab')2 fragment” of an antibody consists of a dimer of two Fab' fragments held together by two disulfide bonds, and is obtained by treating a whole antibody molecule with the enzyme pepsin, without subsequent reduction.
  • A“Fab2” fragment is a recombinant fragment comprising two Fab fragments linked using, for example a leucine zipper or a CH3 domain.
  • A“single chain Fv” or“scFv” is a recombinant molecule containing the Fv of an antibody in which the variable region of the light chain and the variable region of the heavy chain are covalently linked by a suitable, flexible polypeptide linker. As will be apparent from the foregoing discussion, this term encompasses an antibody or an antigen binding fragment thereof comprising a VH and a V L .
  • sequence identity indicates the percentage of amino acids that are identical between the sequences, preferably over the entire length of the amino acid sequences as encoded by SEQ ID NO. 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 24, 25.
  • Preferred, polypeptide sequences of the invention have a sequence identity of respectively at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%.
  • the terms“preventing”,“prevent” or“prevention” include administering a compound of the disclosure to thereby stop or hinder the development or progression of at least one symptom of a condition.
  • the terms“treating”,“treat” or“treatment” include administering a protein described herein to thereby reduce or eliminate at least one symptom of a specified disease or condition or to slow progression of the disease or condition.
  • the term“subject” shall be taken to mean any animal including humans, for example a mammal. Exemplary subjects include but are not limited to humans and nonhuman primates. For example, the subject is a human.
  • the disclosure herein provides a method for treating renal fibrosis and/or chronic kidney disease (CKD) by administering to the subject an inhibitor of Factor XII.
  • CKD chronic kidney disease
  • the disclosure also provides, a method for preventing renal fibrosis and/or CKD in a subject comprising administering to the subject an inhibitor of Factor XII.
  • CKD is a progressive disease that can be subdivided in stages I through V. Depending on the severity of the disease, progression from one stage to another may be slowed down and/or prevented by administering to the subject an inhibitor of Factor XI I.
  • the subject suffers from one or more of the following renal disorders:
  • Kidney allograft injury related to ischemia reperfusion or rejection Kidney allograft injury related to ischemia reperfusion or rejection.
  • the subject has suffered or suffers from a condition associated with renal or kidney fibrosis.
  • the subject has suffered or suffers from diabetes.
  • the methods of the present disclosure can be readily applied to any form of renal disorder associated with renal fibrosis and/or CKD.
  • the subject is at risk of developing renal fibrosis and/or CKD, but the onset of renal fibrosis has not yet occurred.
  • a subject is at risk if he or she has a higher risk of developing renal fibrosis and/or CKD than a control population.
  • the control population may include one or more subjects selected at random from the general population (e.g., matched by age, gender, race and/or ethnicity) who have not suffered from or have a family history of diabetes or other kidney diseases associated with renal fibrosis.
  • a subject can be considered at risk for renal fibrosis and/or CKD if a "risk factor" associated with renal fibrosis and/or CKD is found to be associated with that subject (reduced GFR, proteinuria, diabetes, hypertension, obesity, presence of human leucocyte antibodies in kidney transplant patients).
  • a risk factor can include any activity, trait, event or property associated with a given disorder, for example, through statistical or epidemiological studies on a population of subjects. A subject can thus be classified as being at risk for renal fibrosis even if studies identifying the underlying risk factors did not include the subject specifically.
  • methods of the disclosure achieve one or more of the following effects:
  • a“reduction” or“attenuation” in a symptom or effect of a renal disorder such as renal fibrosis in a subject will be comparative to another subject who has also suffered from a renal disorder such as renal fibrosis but who has not received treatment with a method described herein or to the subject prior to treatment. This does not necessarily require a side-by-side comparison of two subjects. Rather population data can be relied upon.
  • a population of subjects suffering from renal fibrosis who have not received treatment with a method described herein (optionally, a population of similar subjects to the treated subject, e.g., age, weight, diabetic status) are assessed and the mean values are compared to results of a subject or population of subjects treated with a method described herein.
  • Inhibitors of Factor XII are assessed and the mean values are compared to results of a subject or population of subjects treated with a method described herein.
  • the inhibitor of FXII is a direct FXII inhibitor, such as a specific FXII inhibitor.
  • the specific FXII inhibitor inhibits plasmatic serine proteases or other endogenous proteins other than FXII and/or FXIIa less than or equal to about 25% if used in a molar ratio of 1 :1.
  • the specific inhibitor of FXII/FXIIa inhibitor inhibits plasmatic serine proteases other than FXII and/or FXIIa less than or equal to about 25% when said inhibitor is used in a molar ratio of 1 : 1 of the respective plasmatic serine protease to said inhibitor.
  • the FXII inhibitor inhibits plasmatic serine proteases other than FXII and/or FXIIa less than or equal to about 20%, or less than or equal to about 15%, or less than or equal to about 10%, or less than or equal to about 5%, or less than or equal to about 1% if used in a molar ratio of 1 :1.
  • a specific FXII antibody inhibits the plasmatic serine protease FXIa by about 5%, wherein the molar ratio of FXIa to said antibody is 1 :1 whereas the same FXII antibody inhibits FXIIa by at least about 80%, or at least about 90%.
  • one other plasmatic serine protease is inhibited by more than about 50% if used in a molar ratio of 1 :1 of the respective plasmatic serine protease to the inhibitor.
  • two other plasmatic serine proteases are inhibited by more than about 50% if used in a molar ratio of 1 :1 of the respective plasmatic serine protease to the inhibitor.
  • the inhibitor of FXII is a serine protease inhibitor.
  • the inhibitor of FXII comprises a sequence corresponding to lnfestin-4 or variants thereof.
  • the inhibitor of FXII comprises a sequence corresponding to SPINK-1 or variants thereof. lnfestin-4
  • the disclosure provides an inhibitor of FXII comprising infestin domain 4 (referred to as“lnfestin-4”).
  • Infestins are a class of serine protease inhibitors derived from the midgut of the hematophagous insect, Triatoma infestans, a major vector for the parasite Trypanosoma cruzi, known to cause Chagas disease. (Campos ITN et al. 32 Insect Biochem. Mol. Bio. 991-997, 2002; Campos ITN et al. 577 FEBS Lett. 512-516, 2004; WO 2008/098720.) This insect uses these inhibitors to prevent coagulation of ingested blood.
  • the infestin gene encodes 4 domains that result in proteins that can inhibit different factors in the coagulation pathway.
  • domain 4 encodes a protein (lnfestin-4) that is a strong inhibitor of FXIIa.
  • lnfestin-4 has been administered in mice without resulting in bleeding complications (WO 2008/098720; Hagedorn et al., Circulation 2010; 121 : 1510-17.)
  • the inhibitor of FXII comprises lnfestin-4.
  • the term“lnfestin-4,”as used herein, encompasses variants or fragments of the wild-type peptide that retain the ability to inhibit FXII.
  • an exemplary sequence of lnfestin-4 is set out in SEQ ID NO: 1.
  • the lnfestin-4 is chosen for its ability to inhibit FXIIa.
  • the lnfestin-4 comprises a variant of lnfestin-4, wherein the variant comprises Infestin domain 4, and optionally, Infestin domains 1 , 2, and/or 3.
  • the lnfestin-4 is a (His)e- tagged lnfestin-4 construct.
  • the lnfestin-4 is a fusion protein comprising a fusion partner, such as a half-life enhancing polypeptide (e.g., albumin, an Fc domain of an IgG, or PEG), linked or bound to infestin-4.
  • a linker connects the fusion partner to lnfestin-4.
  • the lnfestin-4 is the rH A- lnfestin-4 protein described in Hagedorn et al., Circulation 2010; 117: 1 153-60.
  • a composition comprises albumin bound to the rH A- lnfestin-4 protein described in Hagedorn et al., Circulation 2010; 117: 1153-60, by a flexible linker.
  • other lnfestin-4 inhibitors of FXII are used, examples of which are described in WO 2008/098720 and Hagedorn et al., Circulation 2010; 117: 1 153- 60, both of which are incorporated by reference in their entirety.
  • the inhibitor of FXII is a variant of lnfestin-4.
  • the term “variant” of lnfestin-4 refers to a polypeptide with one or more amino acid mutation, wherein“mutation” is defined as a substitution, a deletion, or an addition, to the wild type lnfestin-4 sequence (SEC ID NO: 1).
  • the term “variant” of lnfestin-4 also includes functional fragments of the wild type or a mutated lnfestin-4 sequence. ln one example, the one or more mutations to the wild type lnfestin-4 sequence do not substantially alter the functional ability of the polypeptide to inhibit FXII.
  • the one or more mutations do not completely or substantially remove the ability of the polypeptide to inhibit FXII.
  • the variant retains at least about 20%, or about 30%, or about 40%, or about 50%, or about 60%, or about 70%, or about 80%, or about 90%, or about 95%, or about 98%, or about 99%, or more of the inhibitory ability of wild type lnfestin-4.
  • the inhibitor of FXII comprises an lnfestin-4 variant comprising residues 2-13 from the amino terminal of the wild type lnfestin-4 sequence as set forth in SEQ ID NO: 1.
  • the lnfestin-4 variant comprises the amino acid sequence set forth in SEQ ID NO: 24.
  • the inhibitor of FXII comprises an lnfestin-4 variant comprising residues 2-13 of SEQ ID NO: 1 and also comprising at least one amino acid mutations, as compared to the wild type lnfestin-4 sequence (SEQ ID NO: 1), outside residues 2-13 of SEQ ID NO: 1.
  • the lnfestin-4 variant comprises at least two amino acid mutations, or at least three amino acid mutations, or at least four amino acid mutations, or at least five amino acid mutations.
  • the inhibitor of FXII comprises a polypeptide sequence comprising SEQ ID NO: 1 modified to contain between 1 and 5 amino acid mutations outside of N-terminal amino acid positions 2-13 of SEQ ID NO: 1.
  • the inhibitor of FXII is an lnfestin-4 variant which retains six conserved cysteine residues from the wild type lnfestin-4 sequence.
  • the six conserved cysteine residues are amino acids at positions 6, 8, 16, 27, 31 , and 48 of the wild type lnfestin-4 sequence (SEQ ID NO: 1).
  • the lnfestin-4 variant comprises the final conserved cysteine at position 48.
  • the exact positions of the cysteine residues, and relative positions to each other may change from positions 6, 8, 16, 27, 31 , and 48 of the wild type lnfestin-4 sequence due to insertions or deletions in the lnfestin-4 variant sequence.
  • the lnfestin-4 variant is at least about 70% identical to the wild type Infestin4 sequence.
  • the lnfestin-4 has an identity of at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% to the wild type lnfestin-4 sequence.
  • the inhibitor of FXII comprises a polypeptide sequence comprising a sequence at least 70% identical to SEQ ID NO: 1 and retaining six conserved cysteine residues from SEQ ID NO: 1.
  • the inhibitor of FXII is an lnfestin-4 variant retains six conserved cysteine residues from the wild type lnfestin-4 sequence and/or has a sequence of at least about 70% identical to the wild type lnfestin-4 sequence.
  • the inhibitor of FXII is an lnfestin-4 variant comprising SEQ ID NO: 1 modified to contain 1-5 amino acid mutations outside of N-terminal amino acid positions 2-13 of SEQ ID NO: 1 ; and a sequence at least 70% identical to SEQ ID NO: 1 and retaining six conserved cysteine residues from SEQ ID NO: 1.
  • mice develop severe interstitial renal fibrosis within 7-10 days after ureter obstruction.
  • mice For the obstruction of the left ureter 2-month-old C57BI/6 mice were anaesthetized with ketamine/xylazine (50 and 5 mg/kg, respectively; Ketavet from Pfizer, Germany and Rompun from Bayer, Germany). The left side was shaved and a midline incision over the left kidney was made. The left ureter was tied off twice with a suture until the endpoint and the incision was closed. During the operation the body temperature was maintained by placing the mice on a 37°C heating pad.
  • mice were sacrificed 10 days after UUO as described in the method section above, and the extent of fibrosis was characterized by morphological and biochemical changes of the targeted organ.
  • Serial sections (2 pm) of paraffin-embedded samples were stained with PAS.
  • the severity of tubulointerstitial lesions was graded from 0 to 5 (normal, mild, moderate, advanced, or severe) using an activity index described previously (Moreth K., et al. J Clin Invest, 2010).
  • T ubular injury scores for each mouse were calculated as the mean of the summed individual scores for each image.
  • Figures 1A and 1 B The results are represented in Figures 1A and 1 B, wherein Figure 1A represents the tubular injury score determined in the control and obstructed (UUO) kidneys from IgG- and 3F7-treated mice at day 10 post injury, and wherein Figure 1 B shows PAS-stained sections from control and obstructed (UUO) kidneys from IgG- and 3F7-treated mice at day 10 post injury.
  • Treatment with the 3F7 antibody markedly reduced the number of atrophic tubules and reduced tubular dilatation in obstructed kidneys from mice treated with the 3F7 antibody vs. IgG treated controls, as can be seen from Figures 1A and 1 B.
  • the inventors performed gene expression profiling on UUO kidney homogenate samples from animals treated with either the anti-FXII antibody (3F7) or the IgG isotype control.
  • the four most upregulated genes in the anti-FXII antibody treated group suggested an impact of the FXII inhibition on: 1) ECM-cell and cell-cell communication: desmoglein 1 gamma (Dsglc), 2) angiogenesis: angiopoietin like 7 (Angptl7), 3) ion homeostasis: anoctamin 2 (Ano2), and 4) transcriptional regulation: regulatory factor X6 (Rfx6) (Table 1)
  • Angptl7 angiopoietin-like 7 1.26 ⁇ 0.62 2.86
  • the experimental results reported herein indicate that 3F7-treatment has effects on gene expression which may explain the reported effects in the experimental animals, for instance the reduction in the number of apoptotic cells (cf. example 5 above), or the aforementioned prevention of loss of functional tubules, reduced evolution of renal fibrosis, and attenuated body- weight loss.

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Abstract

L'invention concerne un inhibiteur du facteur XII (FXII) destiné à être utilisé dans le traitement ou la prévention d'une maladie rénale chronique, d'une fibrose rénale, d'une glomérulosclérose, d'une cicatrice rénale, d'une lésion d'ischémie/reperfusion dans des reins natifs ou transplantés et/ou d'une lésion rénale aiguë, un kit destiné à être utilisé dans le traitement ou la prévention d'une maladie rénale chronique, d'une fibrose rénale, d'une glomérulosclérose, d'une cicatrice rénale, d'une lésion d'ischémie/reperfusion dans des reins natifs ou transplantés, d'une lésion rénale aiguë, d'une fibrose rénale suite au rejet d'une greffe/allogreffe rénale, et/ou d'une fibrose d'une greffe/allogreffe rénale suite au rejet ou à une maladie sous-jacente récurrente comprenant un inhibiteur du facteur XII, et un anticorps anti-Facteur XII (FXII) ou un fragment de liaison à l'antigène de celui-ci pour une utilisation dans le traitement ou la prévention d'une maladie rénale chronique, d'une fibrose rénale, d'une glomérulosclérose, d'une cicatrice rénale, d'une lésion d'ischémie/reperfusion dans des reins natifs ou transplantés et/ou d'une lésion rénale aiguë comprenant un inhibiteur du facteur XII.
PCT/AU2018/051333 2017-12-15 2018-12-14 Utilisation d'un inhibiteur de fxiia dans le traitement d'une fibrose rénale et/ou d'une maladie rénale chronique WO2019113642A1 (fr)

Priority Applications (8)

Application Number Priority Date Filing Date Title
CN201880080931.3A CN111479587B (zh) 2017-12-15 2018-12-14 FXIIa抑制剂在治疗肾纤维化和/或慢性肾脏疾病中的应用
AU2018382222A AU2018382222A1 (en) 2017-12-15 2018-12-14 Use of a FXIIa-inhibitor in the treatment of renal fibrosis and/or chronic kidney disease
US16/772,207 US11505619B2 (en) 2017-12-15 2018-12-14 Use of a FXIIa-inhibitor in the treatment of renal fibrosis and/or chronic kidney disease
KR1020207020386A KR20200100116A (ko) 2017-12-15 2018-12-14 신장 섬유증 및/또는 만성 콩팥 질환의 치료에서 FXIIa-억제제의 용도
CA3085478A CA3085478A1 (fr) 2017-12-15 2018-12-14 Utilisation d'un inhibiteur de fxiia dans le traitement d'une fibrose renale et/ou d'une maladie renale chronique
EP18889862.1A EP3723804A4 (fr) 2017-12-15 2018-12-14 Utilisation d'un inhibiteur de fxiia dans le traitement d'une fibrose rénale et/ou d'une maladie rénale chronique
JP2020531919A JP7317827B2 (ja) 2017-12-15 2018-12-14 腎線維症および／または慢性腎臓疾患の治療におけるＦＸＩＩａインヒビターの使用
BR112020011240-2A BR112020011240A2 (pt) 2017-12-15 2018-12-14 uso de um inibidor de fxiia no tratamento de fibrose renal e/ou doença renal crônica

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WO2021108862A1 (fr) * 2019-12-03 2021-06-10 CSL Innovation Pty Ltd Utilisation d'un anticorps anti-facteur xii pour le traitement ou la prévention de l'oedème de quincke héréditaire
WO2024038282A1 (fr) 2022-08-18 2024-02-22 Kalvista Pharmaceuticals Limited Dérivés de 2-aza- et 2-oxabicyclo[2.1.1]hexane utilisés comme inhibiteurs de l'enzyme du facteur xiia
WO2024084217A1 (fr) 2022-10-19 2024-04-25 Kalvista Pharmaceuticals Limited Dérivés de 3a,4,5,6-tétrahydro-1h-pyrazolo[3,4-c]pyridin-7(7ah)-one utilisés en tant qu'inhibiteurs du facteur xiia

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WO2021108862A1 (fr) * 2019-12-03 2021-06-10 CSL Innovation Pty Ltd Utilisation d'un anticorps anti-facteur xii pour le traitement ou la prévention de l'oedème de quincke héréditaire
CN114761437A (zh) * 2019-12-03 2022-07-15 杰特创新股份有限公司 抗-因子xii抗体用于治疗或预防遗传性血管性水肿的用途
WO2024038282A1 (fr) 2022-08-18 2024-02-22 Kalvista Pharmaceuticals Limited Dérivés de 2-aza- et 2-oxabicyclo[2.1.1]hexane utilisés comme inhibiteurs de l'enzyme du facteur xiia
WO2024084217A1 (fr) 2022-10-19 2024-04-25 Kalvista Pharmaceuticals Limited Dérivés de 3a,4,5,6-tétrahydro-1h-pyrazolo[3,4-c]pyridin-7(7ah)-one utilisés en tant qu'inhibiteurs du facteur xiia

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